Hypothesis & Rationale: The purpose of the study is to evaluate the natural history of Rett syndrome ( RS), and determine if it is a progressive neurodegenerative disorder, or a neurodevelopmental disorder of early infancy followed by a static course. We would also be starting a therapeutic trial of anticholinesterase drugs, such as donezepil (Aricept) to increase brain acetylcholine content which has been shown to be reduced in RS. Nasal biopsies to study olfactory receptor neurons as a neuronal marker for the abnormalities in RS will be pursued. Methodology: The patients are compared at different time points, with a minimum of 2 years between evaluations. Neurological, developmental, neuropsychological, speech, physical & occupational therapies are compared. For more objective evidence, MRI volumetric assessment, EEG, and anthropometric measures are used. Positron Emission Tomography (PET) studies using markers that bind to vesicles containing acetylcholine in synaptic terminals will be performed to confirm reduced brain levels in vivo and justify our treatment approach with donezepil. These studies will also help to determine effectiveness of therapy. Nasal biopsies to determine the status of olfactory receptor neurons as a marker of neuronal dysfunction in RS has been valuable. The marked reduction in mature neurons suggests reduced viability or inability to reach maturity. Future studies will focus on characteristics of these neurons in culture to determine the stage at which pathological changes occur, and interventions required to prevent or overcome them. These results would have implications for future therapy.